Review of Tarceva

Tarceva is an important drug for lung cancer and here is my summary of its use.

1. EGFR Positive Patients Tarcevas effectiveness is primarily determined by the patients EGFR status. Patients with a mutated epidermal growth factor receptor (EGFR) have a response rate of over 60% to Tarceva, more than double that of conventional chemotherapy. In contrast, EGFR negative patients have a response rate of 10% or less, though some argue its has some efficacy in stabilizing disease not reflected in the response rate).

Whether Tarceva should be used first or after chemotherapy is being debated. Clearly it is a central part of treatment for EGFR positive patients.

2. Testing for EGFR Status

EGFR positive patients are generally non-smokers and very light former smokers with adenocarcinoma. However a few smokers are EGFR positive and some non-smokers are not. Testing to confirm the patient's status makes sense.

3. T790M and Met as Sources of Resistance

Sadly resistance frequently appears after patients respond. The cancer finds way to restore the aberrant signaling.

Two primary sources of resistance are the T790M mutation and MET mutation.

4. Testing

Testing to determine the source of resistance and evaluate what drug holds out promise. Drugs may differ as to their effectiveness with each mutation. For example, one study found generally disappointing results with a dual inhibitor called Neratinib, but responses were seen in patients with the rare G719X EGFR mutation, highlighting the importance of obtaining comprehensive genetic information on trials of targeted agents.
Seequist, Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer, J Clin Oncol. 2010 Jun 20; 28(18):3076-83. See also Gazdar, Epidermal growth factor receptor inhibition in Lung Cancer: the Evolving role of Individualized Therapy, Cancer and Metastasis Reviews, Volume 29, Number 1 / March, 2010. Since different drugs impact different areas, testing is increasing being evaluated and used.

5. Initial clinical trials with pan-inhibitors

A new generation of drugs was designed in part to combat this type of resistance. They are called irreversible pan-inhibitors and showed promise in cell studies. (the name irreversible is confusing and refers to its mode of action; one can apparently withdraw from the drug without significant consequences).

After showing promise in cell studies, the drugs have shown only limited effectiveness in human trials. See Yun, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, PNAS February 12, 2008 vol. 105 no. 6, 2070-2075 (analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272.).

6. Combination therapies

Combinations are the latest word on addressing Tarceva resistance:

"In contrast to the reversible TKIs like gefitinib and erlotinib, the second generation EGFR inhibitors, the irreversible TKIs such as CL387,785, EKB-569, PF00299804, BIBW2992, and HKI-272, seem to effectively inhibit EGFR T790M and block the growth of NSCLC cell lines harboring T790M mutations. Preclinical work in mice suggests that irreversible EGFR inhibitors such as HKI-272 might not be potent enough to completely block EGFR T790M signaling in vivo, and the combinational therapy with inhibitors blocking downstream signaling, such as rapamycin, improves efficacy.

Interestingly, a novel EGFR TKI, WZ4002, efficiently inhibits EGFR phosphorylation and induces significant tumor regression in murine models of EGFR T790M. Additionally, HSP90 inhibitors may effectively target EGFR mutants for degradation and thus overcome the T790M mutation. As T790M remains as a good target, a better designed drug or combinational therapeutic strategies are necessary to overcome drug resistance. Ji, Mechanistic insights into acquired drug resistance in epidermal growth factor receptor mutation-targeted lung cancer therapy." Cancer Science, April 27, 2010

7. Use of Other EGFR Drugs Including Erbitux

Since aberrant EGFR signaling appears to be the culprit and EGFR drugs have shown effectiveness, other anti-EGFR drugs like Erbitux are being closely evaluated. Combinations using Erbitux are showing promise, but again the results can vary based upon the specific cellular characteristics of the patient. Regales, Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer, J Clin Invest. 2009 October 1; 119(10): 30003010. See also, Steiner, Tumor Growth Inhibition with Cetuximab and Chemotherapy in NonSmall Cell Lung Cancer Xenografts Expressing Wild-type and Mutated Epidermal Growth Factor Receptor, Clinical Cancer Research March 2007 13; 1540.

Another study suggested combining HKI 272 with a drug called rapamycin, also known as Sirolimus (" the combination of HKI-272 and rapamycin resulted in significant regression of both types of lung tumors. This combination therapy may potentially benefit lung cancer patients with the EGFR T790M mutation.").

Sos, Chemogenomic Profiling Provides Insights into the Limited Activity of Irreversible EGFR Inhibitors in Tumor Cells Expressing the T790M EGFR Resistance Mutation .

There is no consensus on combinations, and sometimes it seems difficult to get two manufacturers of different drugs to get together for a clinical trial. In my view, a careful review of articles combined with testing can increase the patient's chances of finding a beneficial treatment. Understanding the probable source of resistance and selecting a clinical trial or treatment plan which has shown some promise with that particular oncogene makes sense.